Rajesh Bhagat

Regular use of inhaled albuterol and the allergen-induced late asthmatic response

BACKGROUND We have recently demonstrated that a 2-week course of inhaled albuterol 200 micrograms four times daily caused a near doubling of the allergen-induced early asthmatic response. We hypothesized that this might extend to the more clinically relevant late asthmatic response. METHODS We studied 11 patients with atopic asthma who were free from all medications including inhaled beta 2-agonists for more than 4 weeks. We performed a double-blind, random-order, crossover study, comparing the effect of 1-week treatment periods of albuterol 200 micrograms four times daily and placebo 2 puffs four times daily on the early and late asthmatic responses to the same dose of allergen. RESULTS Regular use of albuterol did not influence the baseline forced expiratory volume in 1 second (FEV1) (3.40 vs 3.42 L, p = 0.84) or the baseline methacholine provocative concentration causing a 20% fall in FEV1 (PC20) (geometric mean, 2.4 mg/ml vs 1.9 mg/ml, p = 0.38). However, all aspects of the allergen-induced asthmatic response were increased. After the 1-week albuterol treatment, the early asthmatic response was slightly greater (21.1% vs 17.9% FEV1 fall, p = 0.26), the late response was greater (23.1% vs 13.2% FEV1 fall, p = 0.0027), and the allergen-induced increase in airway responsiveness (change in log methacholine PC20) was greater (0.37 vs 0.20, p = 0.045). CONCLUSIONS One week of albuterol treatment (200 micrograms four times daily) increased the late asthmatic response and allergen-induced increase in airway responsiveness. This suggests that the combination of regular use of inhaled beta 2-agonist and allergen exposure may cause more airway inflammation than allergen exposure alone.

Salbutamol-induced increased airway responsiveness to allergen and reduced protection versus methacholine: Dose response

BACKGROUND Two adverse effects of inhaled beta 2-agonists are increased airway responsiveness to allergen and tolerance to the bronchoprotective effect of beta 2-agonists versus bronchoconstrictors (e.g., methacholine). OBJECTIVE We studied three doses of inhaled salbutamol, 200, 400, and 800 micrograms/day, to determine dose-response curves for these two adverse effects. METHODS Ten atopic patients with mild, stable asthma free of all asthma medications, allergen exposure, and respiratory tract infection for at least 4 weeks participated in a double-blind, random-order, crossover study. There were four 1-week treatment periods with a 1-week washout period: placebo, salbutamol 200 micrograms, 400 micrograms and 800 micrograms per day. After each treatment, we assessed FEV1, bronchodilation 10 minutes after administration of 200 micrograms of salbutamol, methacholine PC20, methacholine dose-shift after administration of 200 micrograms of salbutamol, and allergen PC20. RESULTS There was no significant difference in baseline FEV1, bronchodilation, or methacholine PC20. The methacholine dose shift was maximum after the placebo (3.4 +/- 0.22 doubling doses) and was significantly greater (p < 0.01) than all salbutamol regimens (2.2 to 2.6), which were not significantly different from each other (p > 0.05). Allergen PC20 was significantly lower (p < 0.02) after salbutamol 800 micrograms/day (geometric mean = 288 protein nitrogen units [PNU]/ml) than each of the other treatments (447 to 550 PNU/ml), which were not significantly different from each other (p > 0.05). CONCLUSION Significant increase in airway responsiveness to allergen occurred only with the largest dose of inhaled salbutamol (800 micrograms/d); however, tolerance to the acute bronchoprotective effect of salbutamol was observed with all the three salbutamol regimens, even 200 micrograms/day. This suggests different mechanisms may be operative in producing these two effects.

Allergic bronchopulmonary aspergillosis: the spectrum of computed tomography appearances.

Although computed tomography (CT) of the thorax has been compared to plain chest radiography and bronchography for demonstration of central bronchiectasis (CB) in allergic bronchopulmonary aspergillosis (ABPA), the CT presentation of the disease is yet to be highlighted. With this in view, the CT appearances in 23 patients with ABPA were evaluated. The scans were assessed for bronchial, parenchymal and pleural abnormalities. Central bronchiectasis was identified in all patients, involving 114 (85%) of the 134 lobes and 210 (52%) of the 406 segments studied. Other bronchial abnormalities such as dilated and totally occluded bronchi (11 patients), air-fluid levels within dilated bronchi (five patients), bronchial wall thickening (10 patients) and parallel-line shadows (seven patients) were also observed. Parenchymal abnormalities, which had a predilection for upper lobes, included consolidation in 10 (43%) patients, collapse in four (17%) patients and parenchymal scarring in 19 (83%) patients. A total of six cavities were seen in three (13%) patients, and an emphysematous bullae was detected in one (4%) patient. The pleura was involved in 10 (43%) patients. Ipsilateral pleural effusion with collapse was observed in one patient, while in nine other patients, parenchymal, lesions extended up to the pleura. Concomitant allergic Aspergillus sinusitis (AAS) was also detected in three (13%) of the 23 patients. Computed tomography of the thorax in patients with ABPA provides a sensitive method for the assessment of bronchial, parenchymal and pleural abnormalities, and should constitute a part of the diagnostic work of the disease.

Comparison of 3 different doses of budesonide and placebo on the early asthmatic response to inhaled allergen

BACKGROUND A simple laboratory method to evaluate relative potency of inhaled corticosteroids in asthma would be valuable. Single-dose studies with the allergen-induced late asthmatic response have failed to show a useful dose-response relationship. Treatment for several days with inhaled corticosteroids will also inhibit the allergen-induced early asthmatic response. METHODS Twelve atopic asthmatic subjects were studied during a season when no medications were required except ipratropium bromide as needed. These subjects had positive allergen and methacholine inhalation tests and FEV1 greater than 70% of predicted value. A double-blind, randomized, cross-over study compared placebo and budesonide 100, 200, and 400 microg administered by means of Turbuhaler twice daily for 7 days with 6-day washout periods. Methacholine PC20 was measured before and after 6 days of treatment, and allergen PC15 was measured after 7 days of treatment. RESULTS The allergen PC15 (n = 11) was significantly larger (P = .0001) for all doses of budesonide compared with placebo, but there was no significant difference between the 3 doses of budesonide, and no dose response was demonstrated. The methacholine PC20 was significantly larger after all budesonide treatments compared with placebo (P = .024), but there was no difference between the 3 doses. There was a progressive increase in the allergen PC15 chronologically (sequence effect) that was not explained by improvement in FEV1 or airway responsiveness; sequence effects were not seen for FEV1 or for pretreatment or posttreatment methacholine PC20. Statistical adjustment for sequence effect did not alter allergen PC15 statistics. CONCLUSION A 7-day course of budesonide administered by means of Turbuhaler at 200, 400, or 800 microg per day provided marked and significant inhibition of the allergen-induced early asthmatic response compared with placebo. There was, however, no difference between the 3 doses. Therefore this method with these doses is not useful for providing assessment of relative potency.

Concomitant allergic bronchopulmonary aspergillosis and allergic Aspergillus sinusitis with an operated aspergilloma

The three clinical categories of Aspergillus-related respiratory disorders, allergic bronchopulmonary aspergillosis (ABPA), allergic Aspergillus sinusitis (AAS), and aspergilloma usually remain mutually exclusive. Coexistent ABPA with aspergilloma, though infrequent, has been reported,’ whereas concomitant occurrence of ABPA and AAS is a rarity.’ Furthermore, AJ3PA presenting as a collapsed lung with associated pleural effusion has been documented only once before.3 We describe a case of ABPA with concomitant AAS in a patient who had earlier undergone a lobectomy for severe hemoptysis as a result of an aspergilloma in a bronchiectatic cavity. The patient presented to us with collapse of the left lung

Sleep Disturbances in Clinically Stable Young Asthmatic Adults

BACKGROUND Although nocturnal asthma is a well documented clinical problem, the effect of asthma on sleep itself and morbidity caused thereby have not received adequate attention. It is now recognized that partial sleep deprivation has a considerable effect on human functions. OBJECTIVES With this in view, we conducted a study to determine the occurrence and nature of sleep disturbances in a homogeneous group of patients with clinically stable bronchial asthma in their home environment. METHODS Thirty young adult unmarried university students with clinically stable bronchial asthma attending the Institutes outpatient department were asked to respond to an asthma/sleep questionnaire and were requested to maintain a sleep diary for 1 week. A similar group of 30 unmarried healthy young university students also underwent an identical workup and functioned as controls. Ten subjects from each group maintained a peak expiratory flow rate (PEFR) diary. RESULTS The questionnaire revealed that 28 (93%) of the 30 patients experienced sleep disturbances (average 2.7/subject) as compared to 10 (33%) subjects in the control group (average 0.4/subject). The sleep diary confirmed that 27 (90%) of the 30 patients had sleep disturbances (2.4/subject/wk) as compared with 8 (27%) subjects (0.3/subject/wk) in the control group. These differences were statistically significant. Daytime sleepiness and tiredness (63%) and difficulty in maintaining sleep (60%) along with early morning awakening (46%) were more frequently seen. The asthmatic patients also had a shorter duration of sleep (427 min) as compared with the controls (474 min). These findings were significantly different from the control group. CONCLUSIONS Increased daytime sleepiness and tiredness was perhaps a reflection of the poor quality of sleep experienced by patients with clinically stable asthma. This consequently may lead to impaired daytime performance which can have a potentially serious effect for the patient and society.

Safety and Efficacy of Weekly Oral Oltipraz in Chronic Smokers

Cigarette smoking is thought to contribute to carcinogenesis by formation of DNA adducts of tobacco smoke constituents leading to genotoxic damage. The dithiolethione, oltipraz, is a putative cancer chemopreventive agent that induces phase II detoxifying enzymes in preclinical models and reduces aflatoxin adducts in humans living in areas with high dietary levels. To determine if oltipraz could reduce adduct levels of tobacco smoke constituents in the lungs and other target organs, chronic smokers were enrolled to one of three arms: 400 or 200 mg/wk oral oltipraz or placebo. Endobronchial tissue and bronchoalveolar lavage were done before and after 12 weeks of drug treatment; peripheral blood, urine, and oral saline rinse were also collected. Toxicity was assessed every 4 weeks. Fifty-nine of the 77 enrolled subjects completed the study. Of those receiving oltipraz, 15% experienced grade 2/3 toxicity, which was predominantly gastrointestinal. All subject withdrawals occurred in the oltipraz groups. There was no significant difference between pre- and post-polycyclic aromatic hydrocarbon-DNA adduct levels in lung epithelial cells measured by immunoperoxidase staining between treatment and placebo groups. Likewise, no significant differences were found in polycyclic aromatic hydrocarbon or benzo(a)pyrene-7,8-diol-9,10-epoxide adducts measured in blood, oral lining cells, or bladder lining cells. There was also no increase in mRNA or enzymatic activity of phase II enzymes and no change in glutathione levels. Thus, despite moderate drug-related toxicity, there was no significant effect on pharmacodynamic or surrogate risk biomarkers. Other agents with lower toxicity and greater activity to induce phase II enzymes are needed to definitively test the detoxification-induction paradigm in smokers.

Central bronchiectasis in allergic bronchopulmonary aspergillosis: comparative evaluation of computed tomography of the thorax with bronchography

Demonstration of central bronchiectasis (CB) with normal peripheral bronchi is an essential requirement for the diagnosis of allergic bronchopulmonary aspergillosis (ABPA). Although the results of bronchography remain the gold standard for demonstration of central bronchiectasis they are not always diagnostic. Moreover, it is an unpleasant invasive procedure which may be difficult to perform in a patient of allergic bronchopulmonary aspergillosis with acute severe asthma. In an attempt to find a safe and effective alternative to demonstrate central bronchiectasis computed tomography (CT) of the thorax was evaluated against bronchography. Twenty one patients with allergic bronchopulmonary aspergillosis underwent computed tomography of the thorax followed by bronchography. Of the 378 bronchopulmonary segments available for analysis, 42 had to be excluded because of consolidation or non-filling of the contrast dye, leaving 336 segments for evaluation. CB was identified on CT in all 21 patients. Detailed analysis of the visualized segments revealed that computed tomography (using 8 mm contiguous scans) identified 146 of the 212 segments showing central bronchiectasis on bronchography (sensitivity 70%) and 114 of the 124, read as normal on bronchography (specificity 92%). Supplemental 4 mm scans, used in 8 out of 21 patients improved the overall sensitivity of computed tomography to 83%, whilst the specificity remained unchanged at 92%. Thus, computed tomography of the thorax, being more acceptable to the patient, has the potential of being the investigation of choice for the demonstration of central bronchiectasis in patients with allergic bronchopulmonary aspergillosis.

Sleep-Disordered Breathing Symptoms among African-Americans in the Jackson Heart Study

BACKGROUND Sleep-disordered breathing (SDB) is an increasingly recognized risk factor for cardiovascular disease (CVD). Limited data are available from large African American cohorts. METHODS We examined the prevalence, burden, and correlates of sleep symptoms suggestive of SDB and risk for obstructive sleep apnea (OSA) in the Jackson Heart Study (JHS), an all-African-American cohort of 5301 adults. Data on selected daytime and nighttime sleep symptoms were collected using a modified Berlin questionnaire during the baseline examination. Risk of OSA was calculated according to published prediction model. Age and multivariable-adjusted logistic regression models were used to examine the associations between potential risk factors and measures of sleep. RESULTS Sleep symptoms, burden, and risk of OSA were high among men and women in the JHS and increased with age and obesity. Being married was positively associated with sleep symptoms among women. In men, poor to fair perceived health and increased levels of stress were associated with higher odds of sleep burden, whereas prevalent hypertension and CVD were associated with higher odds of OSA risk. Similar associations were observed among women with slight variations. Sleep duration <7h was associated with increased odds of sleep symptoms among women and increased sleep burden among men. Moderate to severe restless sleep was consistently and positively associated with odds of adverse sleep symptoms, sleep burden, and high risk OSA. CONCLUSIONS Sleep symptoms in JHS had a strong positive association with features of visceral obesity, stress, and poor perceived health. With increasing obesity among younger African Americans, these findings are likely to have broad public health implications.

CT in childhood allergic bronchopulmonary aspergillosis

CT of the thorax done during acute severe asthma in two paediatric patients demonstrated central bronchiectasis, a sine qua non for the diagnosis of allergic bronchopulmonary aspergillosis. Bronchography, regarded as the gold standard, was done subsequently on recovery. A comparative segmental analysis revealed that CT was able to identify immediately 24 of 27 segments which showed central bronchiectasis on bronchography. Early diagnosis with the aid of CT enabled immediate intervention which may have helped to prevent further lung damage in the paediatric patients.